In patients with treatment-resistant depression, a single ketamine infusion shifted belief updating toward a more optimistic bias within 4 hours. This early cognitive change was characterized by stronger asymmetrical reinforcement learning and, after one week of treatment, mediated the clinical antidepressant effect. The findings offer new insights into how fast-acting antidepressants alter cognition, which could be harnessed to promote lasting clinical improvement and treatment responsiveness.
The long-standing hypothesis that depression stems from a deficiency in monoamines (serotonin, norepinephrine, dopamine) has guided antidepressant development, but conventional treatments targeting these systems have limitations. The success of ketamine has revived interest in other substances, including the hallucinogen psilocybin (which targets serotonin 5HT2A receptors) and the neurosteroid brexanolone (a GABA-A receptor modulator). Unlike standard antidepressants, these modulators of glutamatergic, serotonergic, and GABAergic systems produce rapid antidepressant effects within 24 hours to a week. Beyond the search for a "miracle" molecule, these new targets may help identify biomarkers for rapid-acting antidepressants and reshape treatment strategies for mood disorders.